The present invention relates to novel compounds, in particular to novel quinoline derivatives, to processes for the preparation of such compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds in medicine.
The mammalian peptide Neurokinin B (NKB) belongs to the Tachykinin (TK) peptide family which also include Substance P (SP) and Neurokinin A (NKA). Pharmacological and molecular biological evidence has shown the existence of three subtypes of TK receptor (NK1, NK2 and NK3) and NKB binds preferentially to the NK3 receptor although it also recognises the other two receptors with lower affinity (Maggi et al, 1993, J. Auton. Pharmacol., 13, 23-93).
Selective peptidic NK3 receptor antagonists are known (Drapeau, 1990 Regul. Pept., 31, 125-135), and findings with peptidic NK3 receptor agonists suggest that NKB, by activating the NK3 receptor, has a key role in the modulation of neural input in airways, skin, spinal cord and nigro-striatal pathways (Mycrs and Undem, 1993 J. Physiol., 470, 665-679; Counture et al., 1993, Regul. Peptides, 46, 426-429, Mccarson and Krause, 1994, J. Neurosci., 14 (2), 712-720; Arenas et al. 1991, J. Neurosci 18, 2332-8). However, the peptide-like nature of the known antagonists makes them likely to be too labile from a metabolic point of view to serve as practical therapeutic agents.
Copending International Patent Application number PCT/EP98/03014 discloses certain compounds stated to be non-peptide NK-3 antagonists and also to have NK-2 antagonist activity. These compounds are therefore considered to be of potential use in the prevention and treatment of a wide variety of clinical conditions which are characterized by overstimulation of the tachykinin receptors, in particular NK-3 and NK-2.
We have now discovered a further novel class of non-peptide NK-3 antagonists which are far more stable from a metabolic point of view than the known peptidic NK-3 receptor antagonists and are of potential therapeutic utility. These compounds also have NK-2 antagonist activity and are therefore considered to be of potential use in the prevention and treatment of a wide variety of clinical conditions which are characterized by overstimulation of the tachykinin receptors, in particular NK-3 and NK-2.
These conditions include respiratory diseases, such as chronic obstructive pulmonary disease (COPD), asthma, airway hyperreactivity, cough; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis and inflammatory pain; neurogenic inflammation or peripheral neuropathy, allergies such as eczema and rhinitis; ophthalmic diseases such as ocular inflammation, conjunctivitis, vernal conjuctivitis and the like; cutaneous diseases, skin disorders and itch, such as cutaneous wheal and flare, contact dermatitis, atopic dermatitis, urticaria and other eczematoid dermatitis; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systhemic lupus erythematosis; gastrointestinal (GI) disorders and diseases of the GI tract such as disorders associated with the neuronal control of viscera such as ulcerative colitis, Crohn""s disease, irritable bowel syndrome (IBS), gastro-exophageous reflex disease (GERD); urinary incontinence and disorders of the bladder function; renal disorders (hereinafter referred to as the xe2x80x98Primary Conditionsxe2x80x99).
Certain of these compounds also show CNS activity and hence are considered to be of particular use in the treatment of disorders of the central nervous system such as anxiety, depression, psychosis and schizophrenia; neurodegenerative disorders such as AIDS related dementia, senile dementia of the Alzheimer type, Alzheimer""s disease, Down""s syndrome, Huntington""s disease, Parkinson""s disease, movement disorders and convulsive disorders (for example epilepsy); demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis and other neuropathological disorders such as diabetic neuropathy, AIDS related neuropathy, chemotherapy-induced neuropathy and neuralgia; addiction disorders such as alcoholism; stress related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; dysthymic disorders; eating disorders (such as food intake disease); fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders of the blood flow caused by vasodilation and vasospastic diseases such as angina, migraine and Reynaud""s disease and pain or nociception, for example, that is attributable to or associated with any of the foregoing conditions especially the transmission of pain in migraine, (hereinafter referred to as the xe2x80x98Secondary Conditionsxe2x80x99).
The compounds of formula (I) are also considered to be useful as diagnostic tools for assessing the degree to which neurokinin-3 and neurokinin-2 receptor activity (normal, overactivity or underactivity) is implicated in a patient""s symptoms.
According to the present invention there is provided a compound, or a solvate or a salt thereof, of formula (I): 
wherein, Ar is an optionally substituted aryl or a C5-7 cycloalkdienyl group, or an optionally substituted C5-7 cycloalkyl group, or an optionally substituted single or fused ring aromatic heterocyclic group;
R is hydrogen, linear or branched C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkylalkyl;
R1 represents hydrogen or up to three optional substituents selected from the list consisting of: C1-6 alkyl, C1-6 alkenyl, aryl, C1-6 alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamido, sulphonamido, C1-6 alkoxycarbonyl, trifluoromethyl, acyloxy, amino or mono- and di-C1-6 alkylamino;
R2 represents a moiety xe2x80x94(CH2)nxe2x80x94NY1Y2 wherein n is an integer in the range of from 1 to 9, Y1 and Y2 are independently selected from C1-6-alkyl; C1-6 alkyl substituted with hydroxy, alkoxy, C1-6 alkylamino or bis (C1-6 alkyl) amino; C3-6 cycloalkyl; C4-6 azacycloalkyl; C1-6-alkenyl; aryl or aryl-C1-6-alkyl or Y1 and Y2 together with the nitrogen atom to which they are attached represent an optionally substituted N-linked single or fused ring heterocyclic group;
R3 is branched or linear C1-6 alkyl, C3-7 cycloalkyl, C4-7 cycloalkylalkyl, optionally substituted aryl, or an optionally substituted single or fused ring aromatic heterocyclic group; and
R4 represents hydrogen or C1-6 alkyl.
R5 represents hydrogen or halogen.
Preferably R5 represents hydrogen. In another preferred aspect R5 is chloro or bromo.
Suitably, Ar represents optionally substituted phenyl,unsubstituted phenyl or cyclohexyl.
Suitably, Ar represents cyclohexyl.
Preferably Ar is phenyl or cyclohexyl.
Suitably, R represents C1-6 alkyl, for example methyl or ethyl or iso-propyl.
In one preferred aspect, R is ethyl. In another preferred aspect, R is methyl or isopropyl.
Suitably R1 represents hydrogen, C1-6 alkoxy, for example methoxy, or hydroxy.
Preferably, R1 represents hydrogen. In another preferred aspect, R1 is methoxy or hydroxy.
Suitably, NY1Y2 represents an optionally substituted N-linked single or fused ring heterocyclic group.
Suitable N-linked single or fused heterocyclic groups, include groups in which any single or fused ring is saturated or unsaturated and consists of 5- or 6-ring atoms, said ring atoms optionally comprising 1 or 2 additional heteroatoms selected from O or N and wherein one or two ring atoms are optionally substituted with one or two oxo groups or one or two of hydroxy, carboxy, carboxy C1-6 alkyl, C1-6 alkoxycarbonyl, aminocarbonyl, C1-6 alkylcarbonyl optionally substituted with an aromatic heterocyclic group, arylcarbonyl, aryl C1-6 alkylcarbonyl, carboxy C1-6 alklycarbonyl, carboxyarylcarbonyl, amino, C1-6 alkylcarbonylamino, C1-6 alkyl, C1-6 hydroxyalkyl, aryl, aryl, C1-6 alkyl, C3-7 cycloalkyl, optionally substituted C4-7 cycloalkenyl, optionally substituted C4-7 azacycloalkyl, optionally substituted C4-7 diazacycloalkyl, optionally substituted C4-7 oxaazacycloalkyl, optionally substituted C4-7 thiazacycloalkyl, optionally substituted C4-7 thiazacycloalkenyl, C3-7 cycloalkylalkyl, hydroxy C1-6 alkoxy C1-6 alkyl, C1-6 alkoxy C1-6 alkyl, di C1-6 alkylaminocarbonyl, di C1-6 alkylamino C1-6 alkylcarbonyl, optionally substituted C4-7 azacycloalkyl C1-6 alkylcarbonyl, optionally substituted C4-7 diazacycloaklyl C1-6 alkylcarbonyl, optionally substituted C4-7oxaazacycloalkyl C1-6 alkylcarbonyl, optionally susbtituted carboxamidine, C1-6 alkylaminothiocarbonyl, optionally substituted nitrovinyl, aminosulphonyl, di C1-6 alklyaminosulphonyl, or an optionally substituted spiroheterocyclic ring or a single or fused ring aromatic heterocyclic group, or the substituents on adjacent ring atoms form a carbocyclic ring; said aryl or aromatic heterocyclic groups being optionally substituted with one or two C1-6 alkyl, alkoxy, hydroxy, halogen or halogenalkyl groups; wherein, unless otherwise defined optionally substituted means substituted with up to three substituents selected from the list consisting of: amino, alkylamino, alkyl, aryl, heterocyclyl, alkylaryl, aralkyl, oxo, hydroxy and nitrile.
Preferably, the additional heteroatom is N.
Favoured optional substituents for the N-linked single or fused heterocyclic groups are selected from carboxy C1-6 alkyl, aminocarbonyl, C1-6 alkylcarbonyl optionally substituted with an aromatic heterocyclic group, arylcarbonyl, aryl C1-6 alkylcarbonyl, carboxy C1-6 alklycarbonyl, carboxyarylcarbonyl, amino, C1-6 alkylcarbonylamino, C1-6 alkyl, C1-6 hydroxyalkyl, aryl, aryl C1-6 alkyl, C3-7 cycloalkyl, optionally substituted C4-7 cycloalkenyl, optionally substituted C4-7 azacycloalkyl, optionally substituted C4-7 diazacycloalkyl, optionally substituted C4-7 oxaazacycloalkyl, optionally substituted C4-7 thiazacycloalkyl, optionally substituted C4-7 thiazacycloalkenyl, C3-7 cycloalkylalkyl, hydroxy C1-6 alkoxy C1-6 alkyl, C1-6 alkoxy C1-6 alkyl, di C1-6 alkylaminocarbonyl, di C1-6 alkylamino C1-6 alkylcarbonyl, optionally substituted C4-7 azacycloalkyl C1-6 alkylcarbonyl, optionally substituted C4-7 diazacycloaklyl C1-6 alkylcarbonyl, optionally substituted C4-7oxaazacycloalkyl C1-6 alkylcarbonyl, optionally susbtituted carboxamidine, C1-6 alkylaminothiocarbonyl, optionally substituted nitrovinyl, aminosulphonyl, di C1-6 alklyaminosulphonyl, or an optionally substituted spiroheterocyclic ring; wherein, unless otherwise defined optionally substituted means substituted with up to three substituents selected from the list consisting of: amino, alkylamino, alkyl, aryl, heterocyclyl, alkylaryl, aralkyl, oxo, hydroxy, nitrile. Preferred optional substituents for the N-linked single or fused heterocyclic groups include isopropylcarbonyl, hydroxyethyl, cyclohexyl, phenyl, benzyl, isopropyl, phenethyl, 1-piperidinyl, hydroxyethoxyethyl, (4-hydroxy)-1-piperidinyl, 4-piperidinyl, (1-methyl)-4-piperidinyl, dimethylaminomethylcarbonyl, diethylaminoethylcarbonyl, (4-methyl)-1-piperazinylmethylcarbonyl, 4-morpholinylethylcarbonyl, amino, (4-methyl)-1-piperazinyl, 1-piperazinyl, N-methyl-Nxe2x80x2-cyanocarboxamidine, 2-thiazolinyl, pyrrolidinyl-N-cyanomethyleneimine, pyrrolidinyl-N-methylmethyleneimine, 1-pyrrolidinyl-2-nitrovinyl, carboxamidine, carboxyethylcarbonyl, pyrrolidinyl-N-methylsulphonylmethyleneimine, (2-carboxy)-phenylcarbonyl, aminosulphonyl, dimethylaminosulphonyl, carboxymethyl.
When present oxo substituents are preferably alpha to the point of linkage of the N-linked single or fused heterocyclic group.
When a hetero atom of the N-linked single or fused heterocyclic group is substituted, preferred substituents are selected from C1-6 alkyl, hydroxy C1-6 alkyl for example hydroxyethyl, C3-7 cycloalkyl, C3-7 cycloalkylalkyl, aryl and arylalkyl, for example methyl, ethyl, isopropyl, phenyl,phenethyl, or benzyl, optionally substituted C4-7 azacycloalkyl for example 4-piperidinyl or (1-methyl)-4-piperidinyl, dialkylaminoalkylcarbonyl for example dimethylaminomethylcarbonyl or diethylaminoethylcarbonyl, hydroxy C1-6 alkoxy C1-6 alkyl for example hydroxyethoxyethyl, optionally substituted C4-7 diazacycloalkyl C1-6 alkylcarbonyl or C4-7 oxaazacycloalkyl C1-6 alkylcarbonyl for example, (4-methyl)-1-piperazinylmethylcarbonyl, 4-morpholinylethylcarbonyl, optionally substituted carboxamidine for example carboxamidine or N-methyl-Nxe2x80x2-cyanocarboxamidine, or pyrrolidinyl-N-cyanomethyleneimine or pyrrolidinyl-N-methylmethyleneimine or pyrrolidinyl-N-methylsulphonylmethyleneimine, optionally substituted nitrovinyl for example 1-pyrrolidinyl-2-nitrovinyl, optionally substituted C4-7 thiazacycloalkenyl for example 2-thiazolinyl, carboxy C1-6 alklycarbonyl for example carboxyethylcarbonyl, carboxyarylcarbonyl for example (2-carboxy)-phenylcarbonyl, aminosulphonyl, di C1-6 alklyaminosulphonyl for example dimethylaminosulphonyl, carboxy C1-6 alkyl for example carboxymethyl.
Fused heterocyclic groups include groups having one or more rings which share one or more atoms, such as spiro fused rings, or one or more bonds.
A suitable N-linked single ring heterocyclic group comprising a 5-membered saturated heterocyclic ring is a pyrrolidin-1-yl group.
A suitable N-linked single ring heterocyclic group comprising a 6-membered saturated heterocyclic ring is an optionally substituted piperidin-1-yl group, for example a 4-(piperidin-1-yl)piperidin-1-yl group or 4-aminopiperidin-1-yl group.
A suitable N-linked single ring 6-membered saturated heterocyclic group comprising an additional heteroatom is an optionally substituted piperazin-1yl group, for example an optionally substituted 4-alkylpiperazin-1-yl group.
A suitable N-linked fused ring heterocyclic group includes a 5-or 6-membered saturated or unsaturated heterocyclic ring fused to a benzene ring.
A suitable N-linked fused ring heterocyclic group comprising a 6-membered saturated heterocyclic ring fused to a benzene ring is a 2-(1,2,3,4-tetrahydro)isoquinolinyl group.
Suitable, N-linked fused heterocyclic groups include spiro fused groups, for example 1,4-dioxa-8-azaspiro[4.5]dec-8-yl group or 3-oxo-2,8-diazaspiro[4.5]dec-8-yl or 2,4-dioxo-1,3,8-triazaspiro[4.5]dec-8-yl or 2,7-diazaspiro[4.4]non-2-yl or 2,3-dioxa-1,8-diazaspiro[4.5]dec-8-yl.
One preferred value of xe2x80x94NY1Y2 is a piperazin-1-yl group, especially a 4-hydroxyalkylpiperazin-1-yl, or 4-(dialkylaminoalkylcarbonyl)piperazin-1-yl, or 4-(azacycloalkyl)piperazin-1-yl, which piperazinyl group may be substituted or unsubstituted
A particularly preferred value of xe2x80x94NY1Y2 is a group of formula (a), (b) (c) or (d): 
wherein T1 represents isopropylcarbonyl, hydroxyethyl, cyclohexyl, phenyl, benzyl, isopropyl, phenethyl, 1-piperidinyl, hydroxyethoxyethyl, (4-hydroxy)-1-piperidinyl, 4-piperidinyl, (1-methyl)-4-piperidinyl, dimethylaminomethylcarbonyl, diethylaminoethylcarbonyl, (4-methyl)-1-piperazinylmethylcarbonyl, 4-morpholinylethylcarbonyl, amino, (4-methyl)-1-piperazinyl, 1-piperazinyl, N-methyl-Nxe2x80x2-cyanocarboxamidine, 2-thiazolinyl, pyrrolidinyl-N-cyanomethyleneimine, pyrrolidinyl-N-methylmethyleneimine, 1-pyrrolidinyl-2-nitrovinyl, carboxamidine, carboxyethylcarbonyl, pyrrolidinyl-N-methylsulphonylmethyleneimine, (2-carboxy)-phenylcarbonyl, aminosulphonyl, dimethylaminosulphonyl, carboxymethyl. 
wherein T1 together with T2 and the atoms to which each is attached form an optionally substituted single or fused ring heterocyclic group and either T3 together with T4 form an optionally substituted single or fused ring heterocyclic group;
Suitably T1 represents one of the following groups: 
wherein R6 represents H or a lower alkyl, preferably H or methyl, m is an integer from 1 to 5 and R7 and R8 represent a lower alkyl, preferably methyl or ethyl or together form an heterocycle, for example a piperidine, morpholine or optionally substituted piperazine.
Q1 represents 2-phthalic acid, a saturated or unsaturated C1-6 carboxylic acid or an heterocycle for example 2-imidazolyl or thiazolyl.
In a group of formula (a), suitably T1 represents also an heterocycle for example imidazolyl, thiazolyl, pyridyl, pyrimidyl, tetrazolyl or T1 represents an optionally substituted carboxamidine or a corresponding quaternary carboxamidine derivative.
In a group of formula (a) suitable T1 represents also one of the chemical entities below: 
wherein R9 and R10 represent hydrogen, alkyl or together form a 5 to 7 membered ring with the N atom to which they are attached, preferably a pyrrolidin or piperidin ring and R11 represents C1-6 linear or branched alkyl or optionally substituted aryl
wherein Q2 is hydrogen, alkyl, aralkyl, aryl, cyano.
In a group of formula (a) suitable T1 represents also a sulphonamide of formula:
SO2NR12R13
wherein R12 and R13 are independently selected from hydrogen; C1-6 alkyl; optionally substituted aryl or R12 and R13 together with the nitrogen atom to which they are attached represent an optionally substituted N-linked single or fused ring heterocyclic group.
In one particular aspect xe2x80x94NY1Y2 is a moiety of formula (a).
In one particular aspect xe2x80x94NY1Y2 is a moiety of formula (b).
In one particular aspect xe2x80x94NY1Y2 is a moiety of formula (c).
In one particular aspect xe2x80x94NY1Y2 is a moiety of formula (d).
Suitably, R3 is optionally substituted aryl, preferably an unsubstituted aryl group such as a phenyl group.
Suitably, R4 is hydrogen.
Suitably, n is an integer from 1 to 6, favourably 1 to 4 and most preferably 1, 2 or 3.
Favourably, nxe2x80x2 represents 1.
Favourably, nxe2x80x2 represents 2.
Favourably, nxe2x80x2 represents 3.
Preferred compounds of formula (I) are those wherein: Ar is phenyl or cyclohexyl, R is methyl, ethyl, or isopropyl, R1 is hydrogen or methoxy or hydroxy, R2 is a moiety (CH2)n wherein n is 1, 2, 3 or 4, R3 is phenyl and R4 is hydrogen and NY1Y2 is:
(i) an optionally substituted piperazinyl group, especially a moiety of the above defined formula (a);
(ii) a moiety of the above defined formula (b); or
(iii) a moiety of the above defined formula (c); or
(iv) a moiety of the above defined formula (d). Further preferred compounds of formula (I) are those wherein: Ar is phenyl or cyclohexyl, R is methyl, ethyl or isopropyl, R1 is hydrogen, methoxy or hydroxy R2 is a moiety xe2x80x94(CH2)nxe2x80x94NY1Y2 wherein n is 1,R3 is phenyl and R4 is hydrogen and NY1Y2 is:
(i) an optionally substituted piperazinyl group, especially a moiety of the above defined formula (a); or
(ii) a moiety of the above defined formula (b).
In particular should be mentioned the compounds of examples 20, 29, 32, 33, 34, 46, 47, 48, 53, 55, 62, 67, 78, 79, 80, 81 and 95.
The compounds of formula (I) may have at least one asymmetric centrexe2x80x94for example the carbon atom labelled with an asterisk (*) in the compound of formula (I)xe2x80x94and therefore may exist in more than one stereoisomeric form. The invention extends to all such stereoisomeric forms and to mixtures thereof, including racemates. In particular, the invention includes compounds wherein the asterisked carbon atom in formula (I) has the stereochemistry shown in formula (Ia): 
wherein Ar, R, R1, R2, R3, R4 and R5 are as defined in relation to formula (I).
The compounds of formula (I) or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form. By pharmaceutically acceptable form is meant, inter alia, having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
A substantially pure form will generally contain at least 50% (excluding normal pharmaceutical additives), preferably 75%, more preferably 90% and still more preferably 95% of the compound of formula (I) or its salt or solvate.
One preferred pharmaceutically acceptable form is the crystalline form, including such form in pharmaceutical composition. In the case of salts and solvates the additional ionic and solvent moieties must also be non-toxic.
Suitable salts are pharmaceutically acceptable salts.
Suitable pharmaceutically acceptable salts include the acid addition salts with the conventional pharmaceutical acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic and methanesulphonic.
Suitable pharmaceutically acceptable salts include salts of acidic moieties of the compounds of formula (I) when they are present, for example salts of carboxy groups or phenolic hydroxy groups.
Suitable salts of acidic moieties include metal salts, such as for example aluminium, alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)amine, cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl-xcex2-phenethylamine, dehydroabietylamine, N,Nxe2x80x2-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine, quinine or quinoline.
Suitable solvates are pharmaceutically acceptable solvates.
Suitable pharmaceutically acceptable solvates include hydrates.
The term xe2x80x98alkylxe2x80x99 (unless specified to the contrary) when used alone or when forming part of other groups (such as the xe2x80x98alkoxyxe2x80x99 group) includes straight- or branched-chain alkyl groups containing 1 to 12 carbon atoms, suitably 1 to 6 carbon atoms, examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl group.
The term xe2x80x98carbocylicxe2x80x99 refers to cycloalkyl and aryl rings.
The term xe2x80x98cycloalkylxe2x80x99 includes groups having 3 to 12, suitably 4 to 6 ring carbon atoms.
The term xe2x80x98arylxe2x80x99 includes phenyl and naphthyl, preferably phenyl which unless specified to the contrary optionally comprise up to five, preferably up to three substituents selected from halogen, alkyl, phenyl, alkoxy, haloalkyl, hydroxyalkyl, hydroxy, amino, nitro, cyano, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, or alkylcarbonyl groups.
The term xe2x80x98aromatic heterocyclic groupxe2x80x99 includes groups comprising aromatic heterocyclic rings containing from 5 to 12 ring atoms, suitably 5 or 6, and comprising up to four hetero-atoms in the or each ring selected from S, O or N.
Unless specified to the contrary, suitable substituents for any heterocyclic group includes up to 4 substituents selected from the group consisting of: alkyl, alkoxy, aryl and halogen or any two substituents on adjacent carbon atoms, together with the carbon atoms to which they are attached, may form an aryl group, preferably a benzene ring, and wherein the carbon atoms of the aryl group represented by the said two substituents may themselves be substituted or unsubstituted.
When used herein the term xe2x80x9chalogenxe2x80x9d refers to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine or bromine.
When used herein the term xe2x80x9cacylxe2x80x9d includes residues of acids, in particular a residue of a carboxylic acid such as an alkyl- or aryl-carbonyl group.
The invention also provides a process for the preparation of a compound of formula (I), or a salt thereof and/or a solvate thereof, which process comprises reacting a compound of formula (II) or an active derivative thereof: 
wherein Rxe2x80x21, Rxe2x80x22, Rxe2x80x23 and Rxe2x80x25 are R1, R2, R3 and R5 respectively as defined in relation to formula (I) or a group convertible to R1, R2, R3 and R5 respectively; with a compound of formula (III): 
wherein Rxe2x80x2, R4xe2x80x2 and Arxe2x80x2 are R, R4 and Ar as defined for formula (I) or a group or atom convertible to R, R4 and Ar respectively; to form a compound of formula (Ib): 
wherein Arxe2x80x2, Rxe2x80x2, Rxe2x80x21, Rxe2x80x22, Rxe2x80x23, Rxe2x80x24 and Rxe2x80x25 are as defined above, and thereafter carrying out one or more of the following optional steps:
(i) converting any one of Arxe2x80x2, Rxe2x80x2, Rxe2x80x21, Rxe2x80x22, Rxe2x80x23, Rxe2x80x24 and Rxe2x80x25 to Ar, R, R1, R2, R3, R4 or R5 respectively as required, to obtain a compound of formula (I);
(ii) converting a compound of formula (I) into another compound of formula (I); and
(iii) preparing a salt of the compound of formula (I) and/or a solvate thereof.
Suitable groups convertible into other groups include protected forms of said groups.
Suitably Arxe2x80x2, Rxe2x80x2, Rxe2x80x21, Rxe2x80x22, Rxe2x80x23, Rxe2x80x24 or Rxe2x80x25 each represents Ar, R, R1, R2, R3, R4 or R5 respectively or a protected form thereof.
It is favoured if the compound of formula (II) is present as an active derivative.
A suitable active derivative of a compound of formula (II) is a transient activated form of the compound of formula (II) or a derivative wherein the carboxy group of the compound of formula (II) has been replaced by a different group or atom, for example by an acyl halide, preferably a chloride, or an acylazide or a carboxylic acid anhydride.
Other suitable active derivatives include: a mixed anhydride formed between the carboxyl moiety of the compound of formula (II) and an alkyl chloroformate; an activated ester, such as a cyanomethyl ester, thiophenyl ester, p-nitrophenyl ester, p-nitrothiophenyl ester, 2,4,6-trichlorophenyl ester, pentachlorophenyl ester, pentafluorophenyl ester, N-hydroxy-phtalimido ester, N-hydroxypiperidine ester, N-hydroxysuccinimide ester, N-hydroxy benzotriazole ester; alternatively, the carboxy group of the compound of formula (II) may be activated using a carbodiimide or N,Nxe2x80x2-carbonyldiimidazole.
The reaction between the compound of formula (II) or the active derivative thereof and the compound of formula (III) is carried out under the appropriate conventional conditions for the particular compounds chosen. Generally, when the compound of formula (II) is present as an active derivative the reaction is carried out using the same solvent and conditions as used to prepare the active derivative, preferably the active derivative is prepared in situ prior to forming the compound of formula (Ib) and thereafter the compound of formula (I) or a salt thereof and/or a solvate thereof is prepared.
For example, the reaction between an active derivative of the compound of formula (II) and the compound of formula (III) may be carried out:
(a) by first preparing an acid chloride and then coupling said chloride with the compound of formula (III) in the presence of an inorganic or organic base in a suitable aprotic solvent such as dimethylformamide (DMF) at a temperature in a range from xe2x88x9270 to 50xc2x0 C. (preferably in a range from xe2x88x9210 to 20xc2x0 C.); or
(b) by treating the compound of formula (II) with a compound of formula (III) in the presence of a suitable condensing agent, such as for example N,Nxe2x80x2-carbonyl diimidazole (CDI) or a carbodiimide such as dicyclohexylcarbodiimide (DCC) or N-dimethylaminopropyl-Nxe2x80x2-ethylcarbodiimide, preferably in the presence of N-hydroxybenzotriazole (HOBT) to maximise yields and avoid racemization processes (see Synthesis, 453, 1972), or O-benzotriazol-1-yl-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluroniumnhexafluorophosphate (HBTU), in an aprotic solvent, such as a mixture of acetonitrile (MeCN) and tetrahydrofuran (THF), for example a mixture in a volume ratio of from 1:9 to 7:3 (MeCN:THF), at any temperature providing a suitable rate of formation of the required product, such as a temperature in the range of from xe2x88x9270 to 50xc2x0 C., preferably in a range of from xe2x88x9210 to 25xc2x0 C., for example at 0xc2x0 C.
A preferred reaction is set out in Scheme 1 shown below: 
wherein Arxe2x80x2, Rxe2x80x2, Rxe2x80x21, Rxe2x80x22, Rxe2x80x23, Rxe2x80x24 and Rxe2x80x25 are as defined above.
It will be appreciated that a compound of formula (Ib) may be converted to a compound of formula (I), or one compound of formula (I) may be converted to another compound of formula (I) by interconversion of suitable substituents. Thus, certain compounds of formula (I) and (Ib) are useful intermediates in forming other compounds of the present invention.
Accordingly, in a further aspect the invention provides a process for preparing a compound of formula (I), or a salt thereof and/or a solvate thereof, which process comprises converting a compound of the above defined formula (Ib) wherein at least one of Arxe2x80x2, Rxe2x80x2, Rxe2x80x21, Rxe2x80x22, Rxe2x80x23, Rxe2x80x24 or Rxe2x80x25 is not Ar, R, R1, R2, R3, R4 or R5 respectively, thereby to provide a compound of formula (I); and thereafter, as required, carrying out one or more of the following optional steps:
(i) converting a compound of formula (I) into another compound of formula (I); and
(ii) preparing a salt of the compound of formula (I) and/or a solvate thereof.
Suitably, in the compound of formula (Ib) the variables Arxe2x80x2, Rxe2x80x2, Rxe2x80x21, Rxe2x80x22, Rxe2x80x23, Rxe2x80x24 and Rxe2x80x25 are Ar, R, R1, R2, R3, R4 or R5 respectively or they are protected forms thereof.
The above mentioned conversions, protections and deprotections are carried out using the appropriate conventional reagents and conditions and are further discussed below.
A compound of formula (II) or the corresponding alkyl (such as methyl or ethyl) ester wherein n is an integer 1, is prepared by reacting a compound of formula (IV) or the corresponding alkyl (such as methyl or ethyl) ester: 
wherein Rxe2x80x21, Rxe2x80x23 and Rxe2x80x25 are as defined above and L1 represents a halogen atom such as a bromine atom, with a compound of formula (V):
HNYxe2x80x21Yxe2x80x22xe2x80x83xe2x80x83(V)
wherein Yxe2x80x21 and Yxe2x80x22 are respectively Y1 and Y2 as defined in relation to formula (I) or protected forms thereof.
Suitably, Yxe2x80x21 and Yxe2x80x22 are Y1 and Y2.
Suitably, reaction between the compounds of formulae (IV) or the corresponding alkyl (such as methyl or ethyl) ester and (V) is carried out under conventional amination conditions, for example when L1 is a bromine atom then the reaction is conveniently carried out in an aprotic solvent, such as tetrahydrofuran or dimethylformamide at any temperature providing a suitable rate of formation of the required product, usually at ambient temperature; preferably the reaction is carried out in the presence of triethylamine (TEA) or K2CO3.
A compound of formula (IV) or the corresponding alkyl (such as methyl or ethyl) ester is prepared by appropriate halogenation of a compound of formula (VI) or the corresponding alkyl (such as methyl or ethyl) ester: 
wherein Rxe2x80x21, Rxe2x80x23 and Rxe2x80x25 are as defined above in relation to formula (II).
Suitable halogenation reagents are conventional reagents depending upon the nature of the halogen atom required, for example when L1 is bromine a preferred halogenation reagent is N-bromosuccinimide (NBS).
The halogenation of the compound of formula (VI) or the corresponding alkyl (such as methyl or ethyl) ester is carried out under conventional conditions, for example bromination is carried out by treatment with NBS in an inert solvent, such as 1,2-dichloroethane or CH3CN, at any temperature providing a suitable rate of formation of the required product, suitably at an elevated temperature such as a temperature in the range of 60xc2x0 C. to 100xc2x0 C., for example 80xc2x0 C.; preferably the reaction is carried out in the presence of a catalytic amount on benzoyl peroxide.
In the case in which the corresponding alkyl (such as methyl or ethyl) ester of compounds (VI), (IV) and (II) are utilised, an hydrolysis to compound (II) is required before conversion to compound (Ib) in Scheme 1. Such hydrolysis can be carried out under acidic conditions, such 10-36% hydrochloric acid at a temperature in the range between 30 and 100xc2x0 C. A compound of formula (II) wherein Rxe2x80x22 represents xe2x80x94(CH2)2-9xe2x80x94NY1Y2, is conveniently prepared by reacting a compound of formula (VII): 
wherein Rxe2x80x21 and Rxe2x80x25 are as defined in relation to formula (II), with a compound of formula (VIII):
R3xe2x80x2xe2x80x94COxe2x80x94CH2xe2x80x94(CH2)pxe2x80x94T5xe2x80x83xe2x80x83(VIII) 
wherein Rxe2x80x23 is as defined in relation to formula (II), and T5 is a group xe2x80x94NY1Y2 as defined in relation to formula (I) or a protected form thereof or a group convertible thereto, and p is an integer in the range of 2 to 9; and thereafter as required removing any protecting group and/or converting any group T5 to NY1Y2.
The reaction between the compounds of formula (VII) and (VIII) is conveniently carried out using Pfitzinger reaction conditions (see for example J. Prakt. Chem. 33, 100 (1886), J. Prakt. Chem. 38, 582 (1888), J. Chem. Soc. 106 (1948) and Chem. Rev. 35, 152 (1944)), for example in an alkanolic solvent such as ethanol, at any temperature providing a suitable rate of formation of the required product, but generally at an elevated temperature, such as the reflux temperature of the solvent, and preferably in the presence of a base such as potassium hydroxide or potassium tert-butoxide.
Protected forms of xe2x80x94NY1Y2 will vary according to the particular nature of the group being protected but will be chosen in accordance with normal chemical practice.
Groups convertible to xe2x80x94NY1Y2 include groups dictated by conventional chemical practice to be required and to be appropriate, depending upon the specific nature of the xe2x80x94NY1Y2 consideration.
Suitable deprotection methods for deprotecting protected forms of NY1Y2 and conversion methods for converting T5 to NY1Y2 will be those used conventionally in the art depending upon the particular groups under consideration with reference to standard texts such as Greene, T. W. and Wuts, P. G. M. Protective Groups in Organic Synthesis, John Wiley and Sons Inc. New York, 1991 (Second Edt.) or in Kocienski, P. J. Protecting groups. George Thieme Verlag, New York, 1994 and Chemistry of the Amino Group, Patais (Ed.), Interscience, New York 1968; or Advanced Organic Chemistry, March J, John Wiley and Sons, New York, 1992.
A compound of formula (VIII) is prepared from a compound of formula (IX):
R3xe2x80x2xe2x80x94COxe2x80x94CH2xe2x80x94(CH2)pxe2x80x94OHxe2x80x83xe2x80x83(IX) 
wherein Rxe2x80x23 is as defined in relation to formula (II) and p is as defined in relation to formula (VIII), by first halogenating, preferably brominating, or mesylating the compound of formula (IX) and thereafter reacting the halogenation or mesylation product so formed with a compound capable of forming a group T5 so as to provide the required comound of formula (VII).
When T5 is a group xe2x80x94NY1Y2, a compound capable of forming a group T5, is a compound of the above defined formula (V).
The halogenation of the compound of formula (IX) is suitably carried out using a conventional halogenation reagent. Mesylation is conveniently carried out using mesyl chloride in an inert solvent such as methylene dichloride, at a temperature below room temperature, such as 0xc2x0 C., preferably in the presence of triethylamine. The reaction conditions between the compound of formula (IX) and the compound capable of forming a group T5 will be those conventional conditions dictated by the specific nature of the reactants, for example when the T5 required is a group NY1Y2 and the required compound capable of forming a group T5 is a compound of the above defined formula (V), then the reaction between the halogenation or mesylation product of the compound of formula (IX) and the compound of formula (V) is carried out under analogous conditions to those described for the reaction between the compounds of formulae (IV) and (V).
Other compounds capable of forming a group T5 will depend upon the particular nature of T5, but will be those appropriate compounds dictated by conventional chemical practice with reference to standard texts such as Chemistry of the Amino Group, Patais (Ed.), Interscience, New York 1968; and Advanced Organic Chemistry, March J, John Wiley and Sons, New York, 1992.
A compound of formula (IX) may be prepared by reacting a compound of formula (X): 
wherein p is as defined in relation to formula (VIII), with a lithium salt of formula (XI):
Rxe2x80x23Lixe2x80x83xe2x80x83(XI)
wherein Rxe2x80x23 is as defined in relation to formula (II).
The reaction between the compounds of formulae (X) and (XI) can be carried out in an aprotic solvent, such as diethyl-ether at any temperature providing a suitable rate of formation of the required product, usually at a low temperature such as in the range of xe2x88x9210xc2x0 C. to xe2x88x9230xc2x0 C., for example xe2x88x9220xc2x0 C.
The compounds of formula (III) are known commercially available compounds or they can be prepared from known compounds by known methods, or methods analogous to those used to prepare known compounds, for example the methods described in Liebigs Ann. der Chemie, (1936), 523, 199.
Chiral compound of formula (III) wherein Ar is a C5 or C7 cycloalkyl group, R is methyl and R4 is H are described in J. Org. Chem. (1996), 61 (12), 4130-4135. A chiral compound of formula (III) wherein Ar is phenyl, R is isopropyl and R4 is H is a known compound described in for example Tetrahedron Lett. (1994), 35(22), 3745-6.
The compounds of formula (V) are known, commercially available compounds or they can be prepared using methods analogous to those used to prepare known compounds; for example the methods described in the Chemistry of the Amino Group, Patais (Ed.), Interscience, New York 1968; Advanced Organic Chemistry, March J, John Wiley and Sons, New York, 1992 ; J. Heterocyclic Chem. (1990), 27, 1559; Synthesis (1975), 135, Bioorg. Med. Chem. Lett. (1997), 7, 555, or Protective Groups in Organic Synthesis (second edition), Wiley Interscience, (1991) or other methods mentioned herein.
4-amino substituted piperidines are generally prepared by reductive amination of 4oxo-piperidine, or a 4-oxo-piperidine N-substituted with an appropriated protecting group, with an appropriate amine. Typical examples can be found in J. Org. Chem. (1990), 55 (8), 2552-4 or ibid. (1995), 60 (15), 4928-9.
Certain diazaspirononane intermediates used herein are known compounds, for example that used to prepare example 68 is described in J. Med. Chem. (1990), 33 (8), 2270-2275.
The condensation of succinic and phthalic anhydrides used to generate examples 83 and 85-87 is described in J. Indian Chem. Soc. (1979), 56 (2), 171-2. 4-Heterocyclic substituted piperidine as used for the preparation of example 77 are described in U.S. Pat. Nos. 4,329,348A1 9,820,511.
The compounds of formula (VII) are known compounds or they are prepared according to methods used to prepare known compounds for example those disclosed in J. Org. Chem. 21, 171 (1955); J. Org. Chem. 21, 169 (1955).
The compounds of formula (X) and (XI) are known compounds or they are prepared according to methods used to prepare known compounds for example those disclosed by Krow G. R. in Organic Reactions, Vol 43, page 251, John Wiley and Sons Inc. 1994 (for the compounds of formula (X)) and Organometallics in Synthesis, Schlosser M.(Ed), John Wiley and Sons Inc. 1994 (for the compounds of formula (XI)).
Compounds of formula (I) wherein R2 represents a moiety xe2x80x94CH2)nxe2x80x94NY1Y2 and xe2x80x94NY1Y2 is a piperazinyl group of formula (a) can suitably be prepared by reacting a compound of formula XII 
wherein Arxe2x80x2, Rxe2x80x2, Rxe2x80x21, Rxe2x80x22, Rxe2x80x23, Rxe2x80x24 and Rxe2x80x25 are as defined above, with reactive species of formula (XIII), for example: 
wherein L2 and Lxe2x80x22 represent leaving groups such as xe2x80x94SAlkyl or xe2x80x94OAlkyl, preferably xe2x80x94SCH3 and xe2x80x94OButyl and R11 is as defined above.
Mono substitution of compounds of formula (XIII) by a compound of formula (XII) generates news structures bearing still one leaving group, Lxe2x80x22, which can then be reacted with compounds of formula:
HNR9R10
wherein R9 and R10 are as defined above to give the final compounds of formula (I).
Substituted carboxamidinopiperazines are best prepared by reacting compounds of formula (XII) with substituted isothiocyanates following scheme 2 
wherein R12 represents lower alkyl, optionally substituted aryl or aralkyl, followed by the substitution of the group xe2x80x94SCH3, which takes place of the leaving group L2, with a compound of formula
HNR9R10
as mentioned above.
Unsubstituted carboxamidinopiperazines of formula (XVI) 
are prepared by reacting a compound of formula (XII) with the benzotriazole derivative of formula (XVII). 
(Dimethylaminolethylene)dimethylammonium piperazines of formula (XVIII) 
are prepared by heating a compound of formula (XII) with HBTU in the presence of a base, for example TEA, in an appropriate solvent, usually one, or a mixture, of those used in peptide coupling reactions. Compounds of formula (I) wherein R2 represents a moiety xe2x80x94(CH2)nxe2x80x94NY1Y2 and xe2x80x94NY1Y2 is a piperazinyl group of formula (a) wherein T1 represents carboxy, alkoxycarbonyl, optionally substituted alkyl, optionally substituted aryl, aralkyl, cycloalkyl, can suitably be prepared by reacting a compound of formula XII with a compound of formula
T1L3
Wherein T1 represents one of the radicals defined as above and L3 a leaving group for example halogen or sulfonate, preferably chlorine, bromine or mesylate. Compounds of formula (XII) are prepared by removing the protective group of a compound of formula (XIX) 
wherein Arxe2x80x2, Rxe2x80x2, Rxe2x80x21, Rxe2x80x22, Rxe2x80x23, Rxe2x80x24 and Rxe2x80x25 are as defined above and P is an amine protective group, for example fmoc or benzyl, preferably fmoc. The protective group is removed by standard methods described in the literature, for example the fmoc residue is splitted by action of piperidine at room temperature in a solvent like acetonitrile. As hereinbefore mentioned, the compounds of formula (I) may exist in more than one stereoisomeric formxe2x80x94and the process of the invention may produce racemates as well as enantiomerically pure forms. Accordingly, a pure enantiomer of a compound of formula (I) is obtained by reacting a compound of the above defined formula (II) with an appropriate enantiomerically pure primary amine of formula (IIIa) or (IIIc): 
wherein Rxe2x80x2, Rxe2x80x24 and Arxe2x80x2 are as defined above, to obtain a compound of formula (Ixe2x80x2a) or (Ixe2x80x2c): 
wherein Arxe2x80x2, Rxe2x80x2, Rxe2x80x21, Rxe2x80x22, Rxe2x80x23, Rxe2x80x24 and Rxe2x80x25 are as defined above.
Compounds of formula (Ixe2x80x2a) or (Ixe2x80x2c) may subsequently be converted to compounds of formula (Ia) or (Ic) by the methods of conversion mentioned before: 
wherein Ar, R, R1 R2, R3, R4 and R5 are as defined above.
Suitably, in the above mentioned compounds of formulae (Ia), (Ic), (Ixe2x80x2a), (Ixe2x80x2c), (IIIa) and (IIIc) R4 represents hydrogen.
An alternative method for separating optical isomers is to use conventional, fractional separation methods in particular fractional crystallization methods. Thus, a pure enantiomer of a compound of formula (I) is obtained by fractional crystallisation of a diastereomeric salt formed by reaction of the racemic compound of formula (I) with an optically active strong acid resolving agent, such as camphosulphonic acid, in an appropriate alcoholic solvent, such as ethanol or methanol, or in a ketonic solvent, such as acetone. The salt formation process should be conducted at a temperature between 20xc2x0 C. and 80xc2x0 C., preferably at 50xc2x0 C.
In the case in which other basic functionalities, such as primary, secondary or tertiary amine, are present in the molecule, a wider range of optically active acid resolving agents become available, including tartaric acid, O,Oxe2x80x2-di-p-toluoyltartaric acid and mandelic acid.
A suitable conversion of one compound of formula (I) into a further compound of formula (I) involves converting one group R2 into another group R2 by for example:
(i) converting a ketal into a ketone, by such as mild acidic hydrolysis, using for example dilute hydrochloric acid;
(ii) reducing a ketone to a hydroxyl group by use of a borohydride reducing agent;
(iii) converting a carboxylic ester group into a carboxyl group using basic hydrolysis; and/or
(iv) reducing a carboxylic ester group to a hydroxymethyl group, by use of a borohydride reducing agent.
As indicated above, where necessary, the conversion of any group Arxe2x80x2, Rxe2x80x2, Rxe2x80x21 Rxe2x80x22, Rxe2x80x23, Rxe2x80x24 and Rxe2x80x25 into Ar, R, R1, R2, R3, R4 or R5 which as stated above are usually protected forms of Ar, R, R1, R2, R3, R4 or R5 may be carried out using appropriate conventional conditions such as the appropriate deprotection procedure.
It will be appreciated that in any of the above mentioned reactions any reactive group in the substrate molecule may be protected and deprotected according to conventional chemical practice, for example as described by Greene, T. W. and Wuts, P.G.M. Protective Groups in Organic Synthesis, John Wiley and Sons Inc. New York, 1991 (Second Edt.) or in Kocienski, P. J. Protecting groups. George Thieme Verlag, New York, 1994.
Suitable protecting groups in any of the above mentioned reactions are those used conventionally in the art. Thus, for example suitable hydroxyl protecting groups include benzyl or trialkylsilyl groups.
The methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected. Thus for example a benzyloxy group may be prepared by treatment of the appropriate compound with a benzyl halide, such as benzyl bromide, and thereafter, if required, the benzyl group may be conveniently removed using catalytic hydrogenation or a mild ether cleavage reagent such as trimethylsilyl iodide or boron tribromide.
As indicated above, the compounds of formula (I) have useful pharmaceutical properties.
Accordingly the present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use as an active therapeutic substance.
In particular, the present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for the treatment or prophylaxis of the Primary and Secondary Conditions.
The present invention further provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
The present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of the Primary and Secondary Conditions.
As mentioned above the Primary conditions include respiratory diseases, such as chronic obstructive pulmonary disease (COPD), asthma, airway hyperreactivity, cough; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis and inflammatory pain; neurogenic inflammation or peripheral neuropathy, allergies such as eczema and rhinitis; ophthalmic diseases such as ocular inflammation, conjunctivitis, vernal conjuctivitis and the like; cutaneous diseases, skin disorders and itch, such as cutaneous wheal and flare, contact dermatitis, atopic dermatitis, urticaria and other eczematoid dermatitis; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systhemic lupus erythematosis; gastrointestinal (GI) disorders and diseases of the GI tract such as disorders associated with the neuronal control of viscera such as ulcerative colitis, Crohn""s disease, irritable bowel syndrome (IBS), gastro-exophageous reflex disease (GERD); urinary incontinence and disorders of the bladder function; renal disorders.
As mentioned above, the Secondary conditions include disorders of the central nervous system such as anxiety, depression, psychosis and schizophrenia; neurodegenerative disorders such as AIDS related dementia, senile dementia of the Alzheimer type, Alzheimer""s disease, Down""s syndrome, Huntington""s disease, Parkinson""s disease, movement disorders and convulsive disorders (for example epilepsy); demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis and other neuropathological disorders such as diabetic neuropathy, AIDS related neuropathy, chemotherapy-induced neuropathy and neuralgia; addiction disorders such as alcoholism; stress related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; dysthymic disorders; eating disorders (such as food intake disease); fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders of the blood flow caused by vasodilation and vasospastic diseases such as angina, migraine and Reynaud""s disease and pain or nociception, for example, that is attributable to or associated with any of the foregoing conditions especially the transmission of pain in migraine.
Such a medicament, and a composition of this invention, may be prepared by admixture of a compound of the invention with an appropriate carrier. It may contain a diluent, binder, filler, disintegrant, flavouring agent, colouring agent, lubricant or preservative in conventional manner.
These conventional excipients may be employed for example as in the preparation of compositions of known agents for treating the conditions.
Preferably, a pharmaceutical composition of the invention is in unit dosage form and in a form adapted for use in the medical or veterinarial fields. For example, such preparations may be in a pack form accompanied by written or printed instructions for use as an agent in the treatment of the conditions.
The suitable dosage range for the compounds of the invention depends on the compound to be employed and on the condition of the patient. It will also depend, inter alia, upon the relation of potency to absorbability and the frequency and route of administration.
The compound or composition of the invention may be formulated for administration by any route, and is preferably in unit dosage form or in a form that a human patient may administer to himself in a single dosage. Advantageously, the composition is suitable for oral, rectal, topical, parenteral, intravenous or intramuscular administration. Preparations may be designed to give slow release of the active ingredient.
Compositions may, for example, be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, reconstitutable powders, or liquid preparations, for example solutions or suspensions, or suppositories.
The compositions, for example those suitable for oral administration, may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinyl-pyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable setting agents such as sodium lauryl sulphate.
Solid compositions may be obtained by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. When the composition is in the form of a tablet, powder, or lozenge, any carrier suitable for formulating solid pharmaceutical compositions may be used, examples being magnesium stearate, starch, glucose, lactose, sucrose, rice flour and chalk. Tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating. The composition may also be in the form of an ingestible capsule, for example of gelatin containing the compound, if desired with a carrier or other excipients.
Compositions for oral administration as liquids may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; aqueous or non-aqueous vehicles, which include edible oils, for example almond oil, fractionated coconut oil, oily esters, for example esters of glycerine, or propylene glycol, or ethyl alcohol, glycerine, water or normal saline; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
The compounds of this invention may also be administered by a non-oral route. In accordance with routine pharmaceutical procedure, the compositions may be formulated, for example for rectal administration as a suppository. They may also be formulated for presentation in an injectable form in an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable liquid, e.g. sterile pyrogen-free water or a parenterally acceptable oil or a mixture of liquids. The liquid may contain bacteriostatic agents, anti-oxidants or other preservatives, buffers or solutes to render the solution isotonic with the blood, thickening agents, suspending agents or other pharmaceutically acceptable additives. Such forms will be presented in unit dose form such as ampoules or disposable injection devices or in multi-dose forms such as a bottle from which the appropriate dose may be withdrawn or a solid form or concentrate which can be used to prepare an injectable formulation.
The compounds of this invention may also be administered by inhalation, via the nasal or oral routes. Such administration can be carried out with a spray formulation comprising a compound of the invention and a suitable carrier, optionally suspended in, for example, a hydrocarbon propellant.
Preferred spray formulations comprise micronised compound particles in combination with a surfactant, solvent or a dispersing agent to prevent the sedimentation of suspended particles. Preferably, the compound particle size is from about 2 to 10 microns.
A further mode of administration of the compounds of the invention comprises transdermal delivery utilising a skin-patch formulation. A preferred formulation comprises a compound of the invention dispersed in a pressure sensitive adhesive which adheres to the skin, thereby permitting the compound to diffuse from the adhesive through the skin for delivery to the patient. For a constant rate of percutaneous absorption, pressure sensitive adhesives known in the art such as natural rubber or silicone can be used.
As mentioned above, the effective dose of compound depends on the particular compound employed, the condition of the patient and on the frequency and route of administration. A unit dose will generally contain from 20 to 1000 mg and preferably will contain from 30 to 500 mg, in particular 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg. The composition may be administered once or more times a day for example 2, 3 or 4 times daily, and the total daily dose for a 70 kg adult will normally be in the range 100 to 3000 mg. Alternatively the unit dose will contain from 2 to 20 mg of active ingredient and be administered in multiples, if desired, to give the preceding daily dose.
No unacceptable toxicological effects are expected with compounds of the invention when administered in accordance with the invention.
The present invention also provides a method for the treatment and/or prophylaxis of the Primary and Secondary Conditions in mammals, particularly humans, which comprises administering to the mammal in need of such treatment and/or prophylaxis an effective, non-toxic pharmaceutically acceptable amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
The activity of the compounds of the present invention, as NK3 ligands, is determined by their ability to inhibit the binding of the radiolabelled NK3 ligands, [125I]-[Me-Phe7]-NKB or [3H]-Senktide, to guinea-pig and human NK3 receptors (Renzetti et al, 1991, Neuropeptide, 18, 104-114; Buell et al, 1992, FEBS, 299(1), 90-95; Chung et al, 1994, Biochem. Biophys. Res. Commun., 198(3), 967-972).
The binding assays utilized allow the determination of the concentration of the individual compound required to reduce by 50% the [125I]-[Me-Phe7]-NKB and [3H]-Senktide specific binding to NK3 receptor in equilibrium conditions (IC50).
Binding assays provide for each compound tested a mean IC50 value of 2-5 separate experiments performed in duplicate or triplicate. The most potent compounds of the present invention show IC50 values in the range 0.1-1000 nM. The NK3-antagonist activity of the compounds of the present invention is determined by their ability to inhibit senktide-induced contraction of the guinea-pig ileum (Maggi et al, 1990, Br. J. Pharmacol., 101, 996-1000) and rabbit isolated iris sphincter muscle (Hall et al., 1991, Eur. J. Pharmacol., 199, 9-14) and human NK3 receptors-mediated Ca++ mobilization (Mochizuki et al, 1994, .J Biol. Chem., 269, 9651-9658). Guinea-pig and rabbit in-vitro functional assays provide for each compound tested a mean KB value of 3-8 separate experiments, where KB is the concentration of the individual compound required to produce a 2-fold rightward shift in the concentration-response curve of senktide. Human receptor functional assay allows the determination of the concentration of the individual compound required to reduce by 50% (IC50 values) the Ca++ mobilization induced by the agonist NKB. In this assay, the compounds of the present invention behave as antagonists.
The activity of the compounds of the present invention, as NK-2 ligands, is determined by their ability to inhibit the binding of the radiolabelled NK-2 ligands, [125I]-NKA or [3H]-NKA, to human NK-2 receptors (Aharony et al, 1992, Neuropeptide, 23, 121-130).
The binding assays utilized allow the determination of the concentration of the individual compound required to reduce by 50% the [125I]-NKA and [3H]-NKA specific binding to NK2 receptor in equilibrium conditions (IC50).
Binding assays provide for each compound tested a mean IC50 value of 2-5 separate experiments performed in duplicate or triplicate. The most potent compounds of the present invention show IC50 values in the range 0.5-1000 nM, such as 1-1000 nM. The NK-2-antagonist activity of the compounds of the present invention is determined by their ability to inhibit human NK-2 receptor-mediated Ca++ mobilization (Mochizuki et al, 1994, J. Biol. Chem., 269, 9651-9658). Human receptor functional assay allows the determination of the concentration of the individual compound required to reduce by 50% (IC50 values) the Ca++ mobilization induced by the agonist NKA. In this assay, the compounds of the present invention behave as antagonists.
The therapeutic potential of the compounds of the present invention in treating the conditions can be assessed using rodent disease models.
As stated above, the compounds of formula (I) are also considered to be useful as diagnostic tool. Accordingly, the invention includes a compound of formula (I) for use as diagnostic tools for assessing the degree to which neurokinin-3 and neurokinin-2 receptor activity (normal, overactivity or underactivity) is implicated in a patient""s symptoms. Such use comprises the use of a compound of formula (I) as an antagonist of said activity, for example including but not restricted to tachykinin agonist-induced inositol phosphate turnover or electrophysiological activation, of a cell sample obtained from a patient. Comparison of such activity in the presence or absence of a compound of formula (I), will disclose the degree of NK-3 and NK-2 receptor involvement in the mediation of agonist effects in that tissue.
The following Descriptions illustrate the preparation of the intermediates, whereas the following Examples illustrate the preparation of the compounds of the invention.